Deciphering the causal relationship between plasma and cerebrospinal fluid metabolites and glioblastoma multiforme: a Mendelian Randomization study.

BACKGROUND: Glioblastoma Multiforme (GBM) is one of the most aggressive and fatal brain cancers. The study of metabolites could be crucial for understanding GBM's biology and reveal new treatment strategies. METHODS: The GWAS data for GBM were sourced from the FinnGen database. A total of 1400 plasma metabolites were collected from the GWAS Catalog dataset. The cerebrospinal fluid (CSF) metabolites data were collected from subsets of participants in the WADRC and WRAP studies. We utilized the inverse variance weighting (IVW) method as the primary tool to explore the causal relationship between metabolites in plasma and CSF and glioblastoma, ensuring the exclusion of instances with horizontal pleiotropy. Additionally, four supplementary analytical methods were applied to reinforce our findings. Aberrant results were identified and omitted based on the outcomes of the leave-one-out sensitivity analysis. Conclusively, a reverse Mendelian Randomization analysis was also conducted to further substantiate our results. RESULTS: The study identified 69 plasma metabolites associated with GBM. Of these, 40 metabolites demonstrated a significant positive causal relationship with GBM, while 29 exhibited a significant negative causal association. Notably, Trimethylamine N-oxide (TMAO) levels in plasma, not CSF, were found to be a significant exposure factor for GBM (OR = 3.1627, 95% CI = (1.6347, 6.1189), P = 0.0006). The study did not find a reverse causal relationship between GBM and plasma TMAO levels. CONCLUSIONS: This research has identified 69 plasma metabolites potentially associated with the incidence of GBM, among which TMAO stands out as a promising candidate for an early detectable biomarker for GBM.

Unraveling the metabolic pathway of choline-TMA-TMAO: Effects of gypenosides and implications for the therapy of TMAO related diseases.

Trimethylamine-N-oxide (TMAO) has emerged as a promising new therapeutic target for the treatment of central nervous system diseases, atherosclerosis and other diseases. However, its origin in the brain is unclear. Gynostemma pentaphyllum (Thunb.) Makino can reduce the increase of TMAO level caused by a high fat diet. But its effective chemical composition and specific mechanism have not been reported. The study confirmed that TMA was more easily to penetrate blood brain barrier than TMAO, the MAO enzyme was partly involved in the transformation of the TMA in brain, which further supplemented the choline-TMA-TMAO pathway. Based on the above metabolic pathway, using multi-omics approaches, such as microbiodiversity, metagenomics and lipidomics, it was demonstrated that the reduction of plasma TMAO levels by gypenosides did not act on FMO3 and MAO in the pathway, but remodeled the microbiota and affected the trimethylamine lyase needed in the conversion of choline to TMA in intestinal flora. At the same time, gypenosides interfered with enzymes associated with TCA and lipid metabolism, thus affecting TMAO and lipid metabolism. Considering the bidirectional transformation of phosphatidycholine and choline, lipid metabolism and TMAO metabolism could affected each other to some extent. In conclusion, our study revealed the intrinsic correlation between long-term application of gypenosides to lipid reduction and nervous system protection, and explained why gypenosides were used to treat brain diseases, even though they had a poor ability to enter the brain. Besides, it provided a theoretical basis for clinical application of gypenosides and the development of new drugs.

The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer's disease.

BACKGROUND: Trimethylamine N-oxide (TMAO), a small molecule produced by the metaorganismal metabolism of dietary choline, has been implicated in human disease pathogenesis, including known risk factors for Alzheimer's disease (AD), such as metabolic, cardiovascular, and cerebrovascular disease. METHODS: In this study, we tested whether TMAO is linked to AD by examining TMAO levels in cerebrospinal fluid (CSF) collected from a large sample (n = 410) of individuals with Alzheimer's clinical syndrome (n = 40), individuals with mild cognitive impairment (MCI) (n = 35), and cognitively-unimpaired individuals (n = 335). Linear regression analyses were used to determine differences in CSF TMAO between groups (controlling for age, sex, and APOE ε4 genotype), as well as to determine relationships between CSF TMAO and CSF biomarkers of AD (phosphorylated tau and beta-amyloid) and neuronal degeneration (total tau, neurogranin, and neurofilament light chain protein). RESULTS: CSF TMAO is higher in individuals with MCI and AD dementia compared to cognitively-unimpaired individuals, and elevated CSF TMAO is associated with biomarkers of AD pathology (phosphorylated tau and phosphorylated tau/Aß42) and neuronal degeneration (total tau and neurofilament light chain protein). CONCLUSIONS: These findings provide additional insight into gut microbial involvement in AD and add to the growing understanding of the gut-brain axis.

The Gut Microbial Metabolite Trimethylamine-N-Oxide Is Present in Human Cerebrospinal Fluid.

Trimethylamine-N-oxide (TMAO) is a small organic molecule, derived from the intestinal and hepatic metabolism of dietary choline and carnitine. Although the involvement of TMAO in the framework of many chronic diseases has been recently described, no evidence on its putative role in the central nervous system has been provided. The aim of this study was to evaluate whether TMAO is present at detectable levels in human cerebrospinal fluid (CSF). CSF was collected for diagnostic purposes from 58 subjects by lumbar puncture and TMAO was quantified by using liquid chromatography coupled with multiple-reaction monitoring mass spectrometry. The molecule was detected in all samples, at concentrations ranging between 0.11 and 6.43 µmol/L. Further analysis on CSF revealed that a total of 22 subjects were affected by Alzheimer's disease (AD), 16 were affected by non-AD related dementia, and 20 were affected by other neurological disorders. However, the stratification of TMAO levels according to the neurological diagnoses revealed no differences among the three groups. In conclusion, we provide the first evidence that TMAO can be assessed in human CSF, but the actual impact of this dietary metabolite in the patho-physiolgy of the central nervous system requires further study.